Phototherapy for neonatal jaundice is the most widely and frequently used treatment to remove or accelerate the excretion of unconjugated bilirubin and reduce the risk of bilirubin-related neurotoxicity. The long-term objectives of this project are to elucidate the mechanism of phototherapy and define the role of three-dimensional structure in metabolism leading in bilirubin excretion. The proposal focusses on the importance of pigment conformation in the partitioning of photochemical processes and the control of photoproduct development, in the expression of intrinsic macroscopic properties such as hydrophobicity, in binding to proteins involved in transport, in hepatic conjugation and excretion. The specific aims of the project are: 1. To define the three-dimensional stereochemistry of bilirubin and its photoisomers, glucuronides, synthetic analogs and protein-bound pigments by spectroscopic and molecular modeling techniques. 2. To synthesize bilirubin analogs that act as molecular probes of partitioning of photobiologic mechanisms, protein binding selectivity and stereochemistry, hepatic conjugation and excretion. 3. To clarify the influence of pigment structure irradiation wavelength and solvent, lipid or protein environment on the regioselectivity of configurational photoisomerization and the promotion of photocyclization to lumirubin. 4. To elucidate the mechanism of lumirubin formation, evaluate the role of protein (albumins) in chirality transfer during photocyclization, determine the complete stereochemical structure of the optically active product and characterize the autoxidation products by spectroscopic and chemical methods. 5. To investigate structural factors influencing differential rates of hepatic clearance of bilirubin photoisomers, such as the relationship between pigment hydrogen bonding and conformation to differential binding constants, rates of hepatic conjugation and biliary secretion, and diffusion to and through lipid bilayers. 6. To determine the specific structural features of pigment molecules required for facile biliary excretion and hepatic glucuronidation. The studies are relevant to the prevention of neurologic damage in the jaundiced newborn and to our understanding of liver disease. They will improve our knowledge of bilirubin metabolism and lead to more effective methods of phototherapy.